# Chromosomal Instability as a Marker and Mechanism of Radiation Response

> **NIH NIH K08** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $185,220

## Abstract

ABSTRACT
Human Papilloma Virus (HPV) causes nearly 5% of all cancers worldwide and is implicated in 95% of cervical
and 70% of oropharyngeal cancers (OPC). Curative platinum-based chemoradiation is the standard of care for
patients with locally advanced cervical and OPC but patients with cervical cancer have significantly worse
survival despite sharing the same viral etiology. Thus, there are significant differences in the radiation response
between, and within, these two HPV+ cancers yet we continue to treat all patients similarly without consideration
of individual tumor biology. Patients with HPV+ and HPV- cancers are also treated identically despite the
significantly worse outcome of HPV- cancers in both sites. It is therefore imperative to gain a better understanding
of tumor biology in order to tailor radiotherapy to improve patient outcomes and minimize toxicity. Chromosomal
instability (CIN) is an ongoing rate of chromosome missegregation events over the course of multiple cell
divisions, and when increased beyond a certain threshold can lead to cell death due to loss of both copies of
one or more essential chromosomes. We, and others, have shown that very high levels of CIN are associated
with cell death, tumor suppression, and improved prognosis in certain cancers. Moreover, combining two sources
of CIN can increase it beyond the viable threshold resulting in cell death. Because both HPV and radiation induce
certain types of CIN, I hypothesize that cells with pre-existing CIN will be more sensitive to radiation. Additionally,
both CIN and radiation can induce innate and adaptive immune responses which are expected to affect overall
treatment response, but predictive markers and mechanistic insights are lacking. This proposal aims to 1) define
the types and extent of CIN caused by different HPV genotypes and viral oncogene levels, 2) determine if pre-
existing CIN sensitizes HPV+ and HPV- cells to radiation in vitro, in vivo, and in patient tumors, and 3) determine
how CIN affects innate and adaptive immunity in the context of radiation. Together, this proposal aims to
determine HPV+ and HPV- tumor intrinsic and extrinsic factors that affect radiation response such that tumor
and host biology can be incorporated into radiation treatment paradigms to decrease toxicity and increase cure.
Dr. Cosper is a post-doctoral fellow in Radiation Oncology and will use this award to gain expertise in virology,
chromosomal instability and immunology, in order to determine biomarkers that allow for personalization of
radiotherapy. Dr. Cosper’s mentorship team consists of world-renowned experts in HPV virology (Dr. Paul
Lambert), CIN (Dr. Beth Weaver), head and neck cancer radiobiology (Dr. Randall Kimple), and tumor
immunology (Dr. Doug McNeel). The academic environment at the University of Wisconsin is superb, with
abundant resources and collaborative opportunities. Further mentorship and training afforded by this award will
provide Dr. Cosper a uniqu...

## Key facts

- **NIH application ID:** 10301916
- **Project number:** 1K08CA256166-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Pippa F Cosper
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $185,220
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301916

## Citation

> US National Institutes of Health, RePORTER application 10301916, Chromosomal Instability as a Marker and Mechanism of Radiation Response (1K08CA256166-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10301916. Licensed CC0.

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